Not so long ago most viewed atherosclerosis as a bland deposit of lipid clogging arteries. Our understanding of the biology of this disease has burgeoned recently. These investigations have pinpointed inflammation as a central process in all stages of atherosclerosis.
The formation of the early lesions of atherosclerosis involves the recruitment of mononuclear leukocytes including monocytes and T lymphocytes. Pro-inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor, and CD40 ligand (CD154) can induce the expression of adhesion molecules on the endothelial cell surface that bind circulating white blood cells at sites of local arterial inflammation. Chemokines such as MCP-1 direct the transendothelial migration of these adherent monocytes. Indeed, interruption of chemokine signaling inhibits formation of experimental atheroma. Other protein mediators, the colony stimulating factors, such as M-CSF and GM-CSF, also activate macrophages during atherogenesis. Later, leukocytes now resident in the forming lesion may themselves elaborate cytokines, amplifying the regional inflammatory response in the artery wall. Inflammatory mediators such as IL-6 evoke heightened synthesis of the acute phase proteins such as fibrinogen, serum amyloid A, and C-reactive protein from the liver, providing conveniently measured gauges of the inflammatory state of an individual.
Inflammation also regulates the progression of atherosclerosis. Among the products elaborated by macrophages exposed to inflammatory cytokines, growth factors (including platelet-derived and fibroblast growth factor family members) can beckon smooth muscle cells to enter the intima from the underlying media, stimulate their proliferation, and manufacture of extracellular matrix proteins that render the fatty plaque more fibrous. Once established, lesions lead to acute clinical complications because of thrombosis. We have gained considerable insight into the mechanisms of these processes, based on the regulation of the strength of the collagen that protects the plaque from rupture and the factors that govern the plaques thrombotic potential. Indeed, inflammatory mediators govern these mechanisms that underlie the dreaded thrombotic complications, the ultimate expression of this disease.
Thus, from the earliest steps of lesion formation, through the usually prolonged phase of silent or stable progression, up to the acutely occluding thrombus, inflammation orchestrates the complex biology of atherosclerosis.
- Libby, P. (2002). "Atherosclerosis: the new view." Sci Am 286(5): 46-55.
- Libby, P. (2002). "Inflammation in atherosclerosis." Nature 420(6917): 868-74.
- Tardif JC, Heinonen T, Orloff D, Libby P. Vascular biomarkers and surrogates in cardiovascular disease. Circulation 2006;113:2936-2942.
- Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Review. Nat Rev Immunol 2006;6:508-519.
- Libby P. Inflammation in cardiovascular disease: the biological basis of inflammatory biomarkers. Chapter in: Morrow DA, editor. Cardiovascular Biomarkers: Pathophysiology and Disease Management. Humana Press Inc. 2006.